A review of imaging agent development

AAPS Journal

Volumn 11, Issue 2, 2009, Pages 286-299

  Agdeppa, Eric D ^a   Spilker, Mary E ^b  

^a GE HEALTHCARE   (United States)

^b PFIZER INC   (United States)

Author keywords

Drug development; Imaging agent development; PET; SPECT

Indexed keywords

1,4,7,10 TETRAAZACYCLODODECANE 1,4,7,10 TETRAACETIC ACID G 68; 3 N 2 FLUOROETHYL SPIPERONE F 18; 3' FLUOROTHYMIDINE F 18; [2 [[2 [[[3 (4 CHLOROPHENYL) 8 METHYL 8 AZABICYCLO[3.2.1]OCT 2 YL]METHYL](2 MERCAPTOETHYL)AMINO]ETHYL]AMINO]ETHANETHIOLATO]OXOTECHNETIUM TC 99M; CONGO RED; DOPA C 11; ESTRADIOL TC 99M; FLUORINE; FLUORODEOXYGLUCOSE F 18; IMATINIB; RADIOACTIVE IODINE; RADIOPHARMACEUTICAL AGENT; TECHNETIUM 99M; THIOFLAVINE; UNCLASSIFIED DRUG;

CLINICAL EFFECTIVENESS; CLINICAL TRIAL; COST EFFECTIVENESS ANALYSIS; DIAGNOSTIC IMAGING; DRUG DISTRIBUTION; DRUG HALF LIFE; DRUG METABOLISM; DRUG SYNTHESIS; HUMAN; HYDROPHOBICITY; IMAGE QUALITY; LIPOPHILICITY; MATHEMATICAL MODEL; NONHUMAN; POSITRON EMISSION TOMOGRAPHY; REVIEW; SAFETY; SENSITIVITY AND SPECIFICITY; SINGLE PHOTON EMISSION COMPUTER TOMOGRAPHY; VALIDATION PROCESS;

ANIMALS; CLINICAL TRIALS AS TOPIC; CONTRAST MEDIA; DIAGNOSTIC IMAGING; DRUG EVALUATION, PRECLINICAL; HUMANS; MOLECULAR BIOLOGY;

EID: 68249135385     PISSN: 15507416     EISSN: None     Source Type: Journal    
DOI: 10.1208/s12248-009-9104-5     Document Type: Review

References (116)

1. Hargreaves RJ. The role of molecular imaging in drug discovery and development. Clin Pharmacol Ther 2008;83:349-53.
2. Vanderheyden JL. Hands-on molecular imaging: Real-time visualization tools bridge gaps in translational medicine. IDrugs 2008;11:579-83.
3. Weber WA, Czernin J, Phelps ME, Herschman HR. Technology Insight: Novel imaging of molecular targets is an emerging area crucial to the development of targeted drugs. Nat Clin Pract 2008;5:44-54.
4. Weissleder R, Pittet MJ. Imaging in the era of molecular oncology. Nature 2008;452:580-9.
5. Willmann JK, van Bruggen N, Dinkelborg LM, Gambhir SS. Molecular imaging in drug development. Nat Rev Drug Discov 2008;7:591-607.
6. Frank R, Hargreaves R. Clinical biomarkers in drug discovery and development. Nat Rev Drug Discov 2003;2:566-80.
7. US Food and Drug Administration. Challenge and Opportunity on the Critical Path to New Medical Products. 2004. http://www.fda.gov/oc/ initiatives/criticalpath/whitepaper.html Accessed 28 December 2008, part of the FDA's Critical Path Initiative. http://www.fda.gov/oc/initiatives/ criticalpath/. Accessed 28 December 2008.
8. Lanza GM, Winter PM, Caruthers SD, Morawski AM, Schmieder AH, Crowder KC, et al. Magnetic resonance molecular imaging with nanoparticles. J Nucl Cardiol 2004;11:733-43.
9. Morawski AM, Lanza GA, Wickline SA. Targeted contrast agents for magnetic resonance imaging and ultrasound. Curr Opin Biotechnol 2005;16:89-92.
10. Nunn A. From clinical trials to prescriptions. J Nucl Med 2006;47:36N-37N.
11. Lantheus. Cardiolite® [package insert]. N. Billerica, MA, 2003.
12. Kapur A, Latus KA, Davies G, Dhawan RT, Eastick S, Jarritt PH, et al. A comparison of three radionuclide myocardial perfusion tracers in clinical practice: The ROBUST study. Eur J Nucl Med Mol Imaging 2002;29:1608-16.
13. Ghosh PR. FDA approves two new technetium-labeled cardiac agents and a pharmacologic alternative to exercise in stress-thallium studies. J Nucl Med 1991;32:11N, 14N-6N, 19N.
14. Taillefer R, DePuey EG, Udelson JE, Beller GA, Latour Y, Reeves F. Comparative diagnostic accuracy of Tl-201 and Tc-99m sestamibi SPECT imaging (perfusion and ECG-gated SPECT) in detecting coronary artery disease in women. J Am Coll Cardiol 1997;29:69-77.
15. Van den Abbeele AD, Badawi RD. Use of positron emission tomography in oncology and its potential role to assess response to imatinib mesylate therapy in gastrointestinal stromal tumors (GISTs). Eur J Cancer 2002;38(Suppl 5):S60-5.
16. Backer MV, Levashova Z, Patel V, Jehning BT, Claffey K, Blankenberg FG, et al. Molecular imaging of VEGF receptors in angiogenic vasculature with single-chain VEGF-based probes. Nat Med 2007;13:504-9.
17. Paulmurugan R, Gambhir SS. Novel fusion protein approach for efficient high-throughput screening of small molecule-mediating protein-protein interactions in cells and living animals. Cancer Res 2005;65:7413-20.
18. I.M.I. Division. 2008 PET Imaging Market Summary Report, Des Plaines, IL, 2008.
19. I.M.I. Division. 2008 Nuclear Medicine Market Summary Report, Des Plaines, IL, 2008.
20. Beekman F, van der Have F. The pinhole: Gateway to ultra-high-resolution three-dimensional radionuclide imaging. Eur J Nucl Med Mol Imaging 2007;34:151-61.
21. Seo Y, Mari C, Hasegawa BH. Technological development and advances in single-photon emission computed tomography/computed tomography. Semin Nucl Med 2008;38:177-98.
22. Maya Y, Ono M, Watanabe H, Haratake M, Saji H, Nakayama M. Novel radioiodinated aurones as probes for SPECT imaging of beta-amyloid plaques in the brain. Bioconjug Chem 2009;20:95-101.
23. Newberg AB, Wintering NA, Plossl K, Hochold J, Stabin MG, Watson M, et al. Safety, biodistribution, and dosimetry of 123 I-IMPY: A novel amyloid plaque-imaging agent for the diagnosis of Alzheimer's disease. J Nucl Med 2006;47:748-54.
24. Klunk WE, Mathis CA. The future of amyloid-beta imaging: A tale of radionuclides and tracer proliferation. Curr Opin Neurol 2008;21:683-7.
25. Beer AJ, Schwaiger M. Imaging of integrin alphavbeta3 expression. Cancer Metastasis Rev 2008;27:631-44.
26. Dijkgraaf I, Beer AJ, Wester HJ. Application of RGD-containing peptides as imaging probes for alphavbeta3 expression. Front Biosci 2009;14:887-99.
27. Miyazaki M, Lee VS. Nonenhanced MR angiography. Radiology 2008;248:20-43.
28. Potthast S, Maki JH. Non-contrast-enhanced MR imaging of the renal arteries. Magn Reson Imaging Clin N Am 2008;16:573-84.
29. Patterson DM, Padhani AR, Collins DJ. Technology insight: Water diffusion MRI - a potential new biomarker of response to cancer therapy. Nat Clin Pract 2008;5:220-33.
30. Pritchard JF, Jurima-Romet M, Reimer ML, Mortimer E, Rolfe B, Cayen MN. Making better drugs: Decision gates in non-clinical drug development. Nat Rev Drug Discov 2003;2:542-53.
31. Bleicher KH, Bohm HJ, Muller K, Alanine AI. Hit and lead generation: beyond high-throughput screening. Nat Rev Drug Discov 2003;2:369-78.
32. Bach-Gansmo T, Danielsson R, Saracco A, Wilczek B, Bogsrud TV, Fangberget A, et al. Integrin receptor imaging of breast cancer: A proof-of-concept study to evaluate 99m Tc-NC100692. J Nucl Med 2006;47:1434-9.
33. Klunk WE, Engler H, Nordberg A, Wang Y, Blomqvist G, Holt DP, et al. Imaging brain amyloid in Alzheimer's disease with Pittsburgh Compound-B. Ann Neurol 2004;55:306-19.
34. Sirol M, Aguinaldo JG, Graham PB, Weisskoff R, Lauffer R, Mizsei G, et al. Fibrin-targeted contrast agent for improvement of in vivo acute thrombus detection with magnetic resonance imaging. Atherosclerosis 2005;182:79-85.
35. Vanderheyden JL, Liu G, He J, Patel B, Tait JF, Hnatowich DJ. Evaluation of 99m Tc-MAG3-annexin V: Influence of the chelate on in vitro and in vivo properties in mice. Nucl Med Biol 2006;33:135-44.
36. Uppoor RS, Mummaneni P, Cooper E, Pien HH, Sorensen AG, Collins J, et al. The use of imaging in the early development of neuropharmacological drugs: A survey of approved NDAs. Clin Pharmacol Ther 2008;84:69-74.
37. Wong DF, Tauscher J, Grunder G. The role of imaging in proof of concept for CNS drug discovery and development. Neuropsychopharmacology 2009;34:187-203.
38. Lockhart A, Ye L, Judd DB, Merritt AT, Lowe PN, Morgenstern JL, et al. Evidence for the presence of three distinct binding sites for the thioflavin T class of Alzheimer's disease PET imaging agents on beta-amyloid peptide fibrils. J Biol Chem 2005;280:7677-84.
39. Shoghi-Jadid K, Small GW, Agdeppa ED, Kepe V, Ercoli LM, Siddarth P, et al. Localization of neurofibrillary tangles and beta-amyloid plaques in the brains of living patients with Alzheimer disease. Am J Geriatr Psychiatry 2002;10:24-35.
40. Gandy S, Petanceska S. Regulation of Alzheimer beta-amyloid precursor trafficking and metabolism. Biochim Biophys Acta 2000;1502:44-52.
41. Gandy SE, Buxbaum JD, Suzuki T, Ramabhadran TV, Caporaso GL, Nairn AC, et al. The nature and metabolism of potentially amyloidogenic carboxyl-terminal fragments of the Alzheimer beta/A4-amyloid precursor protein: Some technical notes. Neurobiol Aging 1992;13:601-3.
42. Shoghi-Jadid K, Barrio JR, Kepe V, Huang SC. Exploring a mathematical model for the kinetics of beta-amyloid molecular imaging probes through a critical analysis of plaque pathology. Mol Imaging Biol 2006;8:151-62.
43. Shoghi-Jadid K, Barrio JR, Kepe V, Wu HM, Small GW, Phelps ME, et al. Imaging beta-amyloid fibrils in Alzheimer's disease: A critical analysis through simulation of amyloid fibril polymerization. Nucl Med Biol 2005;32:337-51.
44. Simmons MK, Manjeshwar R, Agdeppa ED, Mattheyses RM, Kiehl TR, Montalto MC. A computational positron emission tomography simulation model for imaging beta-amyloid in mice. Mol Imaging Biol 2005;7:69-77.
45. Mijnhout GS, Hoekstra OS, van Lingen A, van Diest PJ, Ader HJ, Lammertsma AA, et al. How morphometric analysis of metastatic load predicts the (un)usefulness of PET scanning: The case of lymph node staging in melanoma. J Clin Pathol 2003;56:283-6.
46. Sweet IR, Cook DL, Lernmark A, Greenbaum CJ, Krohn KA. Non-invasive imaging of beta cell mass: A quantitative analysis. Diabetes Technol Ther 2004;6:652-9.
47. 123 I]iodo-mannose (FIM): Biological evaluation of FIM. Nucl Med Biol 2001;28:679-82.
48. Sair HI, Doraiswamy PM, Petrella JR. In vivo amyloid imaging in Alzheimer's disease. Neuroradiology 2004;46:93-104.
49. Wu C, Pike VW, Wang Y. Amyloid imaging: From benchtop to bedside. Curr Top Dev Biol 2005;70:171-213.
50. Avdeef A. Physicochemical profiling (solubility, permeability and charge state). Curr Top Med Chem 2001;1:277-351.
51. Camenisch G, Folkers G, van de Waterbeemd H. Review of theoretical passive drug absorption models: Historical background, recent developments and limitations. Pharm Acta Helv 1996;71:309-27.
52. Jolliet-Riant P, Tillement JP. Drug transfer across the blood-brain barrier and improvement of brain delivery. Fundam Clin Pharmacol 1999;13:16-26.
53. Tanaka H, Mizojiri K. Drug-protein binding and blood-brain barrier permeability. J Pharmacol Exp Ther 1999;288:912-8.
54. van de Waterbeemd H, Smith DA, Jones BC. Lipophilicity in PK design: methyl, ethyl, futile. J Comput Aided Mol Des 2001;15:273-86.
55. Dilworth J, Parrott S. The biomedical chemistry of technitium and rhenium. Chem Soc Rev 1998;27:43-55.
56. 11 C-labelled L-DOPA and l -fluorodopa as PET tracers for the presynaptic dopaminergic system. J Cereb Blood Flow Metab 1999;19:1142-9.
57. Seevers R Counsell R. Radioiodination techniques for small organic molecules. Chem Rev 1982;32:575-90.
58. 11 C-carbamoyl compounds. J Org Chem 2002;67:3687-92.
59. 11 C]methane. Appl Radiat Isot 1997;48:153-7.
60. Kung MP, Kung HF. Mass effect of injected dose in small rodent imaging by SPECT and PET. Nucl Med Biol 2005;32:673-8.
61. 64 Cu-labeled Abegrin, a humanized monoclonal antibody against integrin alpha v beta 3. Cancer Res 2006;66:9673-81.
62. Machac J, Krynyckyi B, Kim C. Peptide and antibody imaging in lung cancer. Semin Nucl Med 2002;32:276-92.
63. Sosnovik DE, Nahrendorf M, Weissleder R. Magnetic nanoparticles for MR imaging: Agents, techniques and cardiovascular applications. Basic Res Cardiol 2008;103:122-30.
64. Waters EA, Wickline SA. Contrast agents for MRI. Basic Res Cardiol 2008;103:114-21.
65. Wickline SA, Lanza GM. Nanotechnology for molecular imaging and targeted therapy. Circulation 2003;107:1092-5.
66. 11C- N -desmethyl-loperamide in monkeys. J Nucl Med 2009;50:108-15.
67. McParland BJ, Miller MP, Spinks TJ, Kenny LM, Osman S, Khela MK, et al. The biodistribution and radiation dosimetry of the Arg-Gly-Asp peptide 18 F-AH111585 in healthy volunteers. J Nucl Med 2008;49:1664-7.
68. Stabin MG, Sparks RB, Crowe E. OLINDA/EXM: The second-generation personal computer software for internal dose assessment in nuclear medicine. J Nucl Med 2005;46:1023-7.
69. Hinz R, Bhagwagar Z, Cowen PJ, Cunningham VJ, Grasby PM. Validation of a tracer kinetic model for the quantification of 5-HT(2A) receptors in human brain with [(11) C]MDL 100,907. J Cereb Blood Flow Metab 2007;27:161-72.
70. Mankoff DA, Shields AF, Graham MM, Link JM, Eary JF, Krohn KA. Kinetic analysis of 2-[carbon-11]thymidine PET imaging studies: Compartmental model and mathematical analysis. J Nucl Med 1998;39:1043-55.
71. 11 C]thymidine PET imaging studies: validation studies. J Nucl Med 1999;40:614-24.
72. Muzi M, Mankoff DA, Grierson JR, Wells JM, Vesselle H, Krohn KA. Kinetic modeling of 3'-deoxy-3'-fluorothymidine in somatic tumors: Mathematical studies. J Nucl Med 2005;46:371-80.
73. Muzi M, Vesselle H, Grierson JR, Mankoff DA, Schmidt RA, Peterson L, Wells JM, et al. Kinetic analysis of 3'-deoxy-3'-fluorothymidine PET studies: Validation studies in patients with lung cancer. J Nucl Med 2005;46:274-82.
74. 99m Tc]TRODAT-1 binding to dopamine transporters in nonhuman primates using single-photon emission tomography. Eur J Nucl Med 1999;26:518-26.
75. Mintun MA, Raichle ME, Kilbourn MR, Wooten GF, Welch MJ. A quantitative model for the in vivo assessment of drug binding sites with positron emission tomography. Ann Neurol 1984;15:217-27.
76. Slifstein M, Laruelle M. Models and methods for derivation of in vivo neuroreceptor parameters with PET and SPECT reversible radiotracers. Nucl Med Biol 2001;28:595-608.
77. Gambhir SS, Barrio JR, Phelps ME, Iyer M, Namavari M, Satyamurthy N, et al. Imaging adenoviral-directed reporter gene expression in living animals with positron emission tomography. Proc Natl Acad Sci U S A 1999;96:2333-8.
78. Melega WP, Luxen A, Perlmutter MM, Nissenson CH, Phelps ME, Barrio JR. Comparative in vivo metabolism of 6-[18 F]fluoro- l -DOPA and [3H] l -DOPA in rats. Biochem Pharmacol 1990;39:1853-60.
79. 18 F-fluorocyclobutyl-1-carboxylic acid for the detection of prostate cancer. J Nucl Med 2007;48:46-55.
80. Bacskai BJ, Frosch MP, Freeman SH, Raymond SB, Augustinack JC, Johnson KA, et al. Molecular imaging with Pittsburgh Compound B confirmed at autopsy: A case report. Arch Neurol 2007;64:431-4.
81. Bergstrom M, Awad R, Estrada S, Malman J, Lu L, Lendvai G, et al. Autoradiography with positron emitting isotopes in positron emission tomography tracer discovery. Mol Imaging Biol 2003;5:390-6.
82. Ferrier MC, Sarin H, Fung SH, Schatlo B, Pluta RM, Gupta SN, et al. Validation of dynamic contrast-enhanced magnetic resonance imaging-derived vascular permeability measurements using quantitative autoradiography in the RG2 rat brain tumor model. Neoplasia (New York, NY) 2007;9:546-55.
83. Ikonomovic MD, Klunk WE, Abrahamson EE, Mathis CA, Price JC, Tsopelas ND, et al. Post-mortem correlates of in vivo PiB-PET amyloid imaging in a typical case of Alzheimer's disease. Brain 2008;131:1630-45.
84. Klunk WE, Debnath ML, Pettegrew JW. Development of small molecule probes for the beta-amyloid protein of Alzheimer's disease. Neurobiol Aging 1994;15:691-8.
85. Tubis M, Blahd W, Nordyke R. The preparation and use of radioiodinated Congo red in detecting amyloidosis. J Am Pharm Assoc 1960;49:422-5.
86. Hyman BT, Bacskai BJ, Kajdasz ST, McLellan ME, Irizarry MC, Frosch M, et al. Imaging Aαplaques in living transgenic mice with multiphoton microscopy using the peripherally administered Congo red analog, methoxy-X04. Abstr Soc Neurosci 2001;27:1217.
87. Zhuang ZP, Kung MP, Hou C, Plossl K, Skovronsky D, Gur TL, et al. IBOX(2-(4'-dimethylaminophenyl)-6-iodobenzoxazole): A ligand for imaging amyloid plaques in the brain. Nucl Med Biol 2001;28:887-94.
88. Engler H, Blomqvist G, Bergstrom M, Estrada S, Sandell J, Antoni G, et al. First human study with a benzothiazole amyloid-imaging agent in Alzheimer's disease and control subjects. Neurobiol Aging 2002;23(Suppl 1):S429.
89. Engler H, Forsberg A, Almkvist O, Blomquist G, Larsson E, Savitcheva I, et al. Two-year follow-up of amyloid deposition in patients with Alzheimer's disease. Brain 2006;129:2856-66.
90. Klunk WE, Wang Y, Huang GF, Debnath ML, Holt DP, Mathis CA. Uncharged thioflavin-T derivatives bind to amyloid-beta protein with high affinity and readily enter the brain. Life Sci 2001;69:1471-84.
91. Mathis CA, Wang Y, Klunk WE. Imaging beta-amyloid plaques and neurofibrillary tangles in the aging human brain. Curr Pharm Des 2004;10:1469-92.
92. Mathis C, Lopresti B, Mason N, Price J, Flatt N, Bi W, et al. Comparison of the amyloid imaging agents [F-18]3'-F-PIB and [C-11]PIB in Alzheimer's disease and control subjects. J Nucl Med 2007;48(Supplement 2):56P.
93. Salvadori P. Radiopharmaceuticals, drug development and pharmaceutical regulations in Europe. Curr Radiopharm 2008;1:7-11.
94. VanBrocklin H. Radiopharmaceuticals for drug development: United States regulatory perspective. Curr Radiopharm 2008;1:2-6.
95. Henderson JA, Alexander BC, Smith JJ. The food and drug administration and molecular imaging agents: Potential challenges and opportunities. J Am Coll Radiol 2005;2:833-40.
96. Hoffman JM, Gambhir SS, Kelloff GJ. Regulatory and reimbursement challenges for molecular imaging. Radiology 2007;245:645-60.
97. Barrio JR, Marcus CS, Hung JC, Keppler JS. A rational regulatory approach for positron emission tomography imaging probes: From "first in man" to NDA approval and reimbursement. Mol Imaging Biol 2004;6:361-7.
98. McEwan A, Van Brocklin H, Divgi C. Action plan for emerging molecular imaging technologies. J Nucl Med 2008;49:37N-40N.
99. Skovronsky D. Use of eINDs for evaluation of multiple related PET amyloid plaque imaging agents. J Nucl Med 2008;49:47N-48N.
100. Hillman BJ, Gatsonis CA. When is the right time to conduct a clinical trial of a diagnostic imaging technology. Radiology 2008;248:12-5.
101. DHHS, FDA, CDER, and CBER, editors. Guidance for industry. Developing medical imaging drug and biological products. Part 2: Clinical indications. 2004, June.
102. Dorfman GS, Sullivan DC, Schnall MD, Matrisian LM. The Translational Research Working Group developmental pathway for image-based assessment modalities. Clin Cancer Res 2008;14:5678-84.
103. Siegel BA, Dehdashti F. Oncologic PET/CT: Current status and controversies. Eur Radiol 2005;15(Suppl 4):D127-32.
104. Atcher R, Graham M, McEwan A. Clinical trial development of nonproprietary imaging agents. J Nucl Med 2008;49:26N.
105. Yu EY, Mankoff DA. Positron emission tomography imaging as a cancer biomarker. Expert Rev Mol Diagn 2007;7:659-72.
106. Hillner BE, Liu D, Coleman RE, Shields AF, Gareen IF, Hanna L, et al. The National Oncologic PET Registry (NOPR): Design and analysis plan. J Nucl Med 2007;48:1901-8.
107. Miller AB, Hoogstraten B, Staquet M, Winkler A. Reporting results of cancer treatment. Cancer 1981;47:207-14.
108. Michaelis LC, Ratain MJ. Measuring response in a post-RECIST world: From black and white to shades of grey. Nat Rev Cancer 2006;6:409-14.
109. Von Hoff D. There are no bad anticancer agents, only bad clinical trial designs - twenty-first Richard and Hinda Rosenthal Foundation Award Lecture. Clin Canc Res 1998;4:1079-86.
110. O'Connell M. PET-CT modification of RECIST guidelines. J Natl Cancer Inst 2004;96:801-2. author reply 802.
111. Frank R, Långström B, Antoni G, Montalto M, Agdeppa E, Mendizabal M, et al. The imaging continuum: Bench to biomarkers to diagnostics. J Label Compd Radiopharm 2007;50:746-69.
112. Frangioni JV. The impact of greed on academic medicine and patient care. Nat Biotechnol 2008;26:503-7.
113. Workman P, Aboagye EO, Chung YL, Griffiths JR, Hart R, Leach MO, et al. Minimally invasive pharmacokinetic and pharmacodynamic technologies in hypothesis-testing clinical trials of innovative therapies. J Natl Cancer Inst 2006;98:580-98.
114. Conti PS, White C, Pieslor P, Molina A, Aussie J, Foster P. The role of imaging with (111) In-ibritumomab tiuxetan in the ibritumomab tiuxetan (zevalin) regimen: Results from a Zevalin Imaging Registry. J Nucl Med 2005;46:1812-8.
115. 18 F]-misonidazole positron emission tomography-detected tumor hypoxia in patients with advanced head and neck cancer randomly assigned to chemoradiation with or without tirapazamine: A substudy of Trans-Tasman Radiation Oncology Group Study 98.02. J Clin Oncol 2006;24:2098-104.
116. Bergstrom M, Grahnen A, Langstrom B. Positron emission tomography microdosing: A new concept with application in tracer and early clinical drug development. Eur J Clin Pharmacol 2003;59:357-66.